1. Field of the Invention
This invention relates generally to a diffusion-controlled dosage form and more particularly to a three-dimensionally printed polymer containing shell dosage form allowing diffusion controlled release of an Active Pharmaceutical Ingredient.
2. Description of the Related Art
There are at least two physical mechanisms that can be important in controlled release drug delivery, namely erosion and diffusion. Erosion involves the physical removal of both Active Pharmaceutical Ingredient (API) and excipient from a dosage form, such as by dissolution in bodily fluids or by degradation by bodily fluids. In an erosion-dominated dosage form, at the conclusion of release, the dosage form essentially no longer exists as an intact solid unit.
The other physical mechanism which is sometimes used in controlled release drug delivery is diffusion. Diffusion involves the passage of API out of the dosage form, while the non-API material of the dosage form substantially remains in the dosage form. Diffusion is governed by concentration gradients and diffusivities. At the end of release of API from a diffusion-controlled dosage form, the dosage form has approximately the same overall dimensions as it did at the time of administration to the patient, but the API has passed out of the dosage form by diffusion. Such a dosage form may pass completely through the digestive tract of the patient retaining approximately its original dimensions. As an example of diffusion-controlled dosage forms, oral dosage forms have been fabricated with an API-containing interior and a coating which has been a release barrier. The release barrier has been permeable to water and digestive fluids, while not being soluble in these liquids. Ingestion of the dosage form by the patient has resulted in water diffusing through the release barrier and beginning to dissolve the API inside the dosage form. The dissolved API has then diffused outward through the release barrier into the patient's digestive system. The release barrier has typically been a single substance which has had a desired permeability for water or aqueous solutions of interest and typically has had a thickness of less than approximately 50 micrometers. Diffusion-controlled release has usually required that the release barrier be substantially free of macroscopic defects. A variation of this, which is a release barrier having microporosity, has been created by depositing, onto the surface of a pre-manufactured tablet, a coating containing both an insoluble substance and micronized sugar. The sugar eventually dissolved out leaving a micro-porous membrane that controlled diffusion of the contents of the interior of the dosage form.
There have also been dosage forms that comprise a diffusion barrier that covers some but not all of the surfaces of the dosage form. In such a dosage form, the barrier has not completely controlled diffusion.
Another controlled release dosage form involving diffusion has been a device known as an osmotic pump. Such devices have been constructed from a core containing the API, a selectively impermeable coating with a defined exit orifice, and a hygroscopic salt or other material which has swelled when wet and has squeezed the API out through the orifice.
Up until the present time, manufacturing diffusion-controlled dosage forms has involved multiple manufacturing processes, one process to manufacture the interior, and another process to apply a coating or release barrier that controls the release. For example, applying the release barrier has been performed by creating a liquid layer around the outside of an already-formed dosage form, and allowing the liquid to dry, or by fluidized bed methods or by pan-coating. This has involved a multi-step manufacturing sequence including two significantly different types of manufacturing processes and typically using different raw materials for each of the manufacturing processes. In the case of the osmotic pump, in addition to the multi-step manufacturing process already described and the need for the film to be defect free other than at the defined exit orifice, this type of dosage form has suffered from the need for an exact size orifice.
FIGS. 1A and 1B illustrate the three-dimensional printing process. Three-dimensional printing (3DP) has sometimes been used to make dosage forms. The ability of 3DP to deposit specific quantities and compositions of material in specific places has provided the ability to design and manufacture dosage forms in a detailed way which has not been achievable with other dosage form manufacturing techniques. Three-dimensional printing has, for example, been used to make a dosage form with a core-and-shell geometry as disclosed in Pending U.S. application Ser. No. 09/861,480, entitled “Method and form of a drug delivery device such as encasing a hazardous core within a pharmacologically inert substance in an oral dosage form.” Core-and-shell dosage forms have also been described in “Application of Polymers in CAD/CAM Processing of Pharmaceutical Products,” AAPS, October 2000. These disclosures do not solve the problems of the present invention. For example, the AAPS disclosure used a shell to control diffusion, however, the shell was not perforation-free and it did not have the ability to closely and repeatably control the release profile.
Porosity has existed in many 3DP printed parts in most industries, but the existence of porosity has often been considered a disadvantage, because for many purposes solid parts have really been what have been desired. For dosage forms, porosity may be useful. However, for diffusion-controlled dosage forms, porosity would only be useful if it could be closely controlled. In order to use 3DP to make a diffusion-controlled dosage form, one choice would be that the shell would have to be made with a controlled porosity in order to achieve a desired diffusivity, which has been difficult. The other choice would be that the shell would have to be made essentially free of macroscopic defects and porosity, and then a controlled amount of porosity or diffusivity would have to be introduced or created. Making the defect-free shell by 3DP has not been achieved, either. Until the present invention, it simply has not been possible to make a dosage form shell by three-dimensional printing that is sufficiently continuous (solid) to be a part of accurately controlling the release by diffusion from a dosage form. More particularly, it has been difficult to make a sufficiently solid shell while leaving other portions of the article porous. Thus, until now, the possibility of single-process manufacturing and the ability for precise design of a dosage form, both of which might be achieved by 3DP, have been essentially unavailable for making diffusion-controlled dosage forms.
For a dosage form governed by diffusion, the natural release profile is that the cumulative amount of API released is proportional to the square root of time since initiation of release, i.e., Q=k*t0.5. The release rate of such a dosage form is the derivative of this function, namely: r=k′*t−0.5, which is a release rate that decreases with time. However, for many API, a desirable release profile would be to release API in approximately a constant release rate, which is a zero-order release. In most cases, diffusion-controlled dosage forms have not provided release profiles that are sufficiently close to a zero-order release profile.
Accordingly, it would be desirable to be able to make diffusion-controlled dosage forms by a single-process manufacturing scheme, i.e., to make both the core and the shell approximately simultaneously by a single process. It would be desirable to provide a powder-based manufacturing process that uses only a single powder and yet can achieve shell properties that are different from the core properties. It would be desirable to make a three-dimensionally printed dosage form which comprises a substantially solid, non-porous shell even while other portions of the dosage form have porosity. It would be desirable to provide a three-dimensionally printed dosage form that contains a shell capable of accurately controlling the release of API by diffusion through the shell. It would be desirable for a manufacturing process to permit adjustment of the time scale of the release profile of a dosage form by a simple adjustment of the composition of powder that is used in the manufacturing process. It would also be desirable to provide a nearly zero-order release profile from a diffusion-controlled dosage form. Diffusion-controlled dosage forms of the type described would be especially useful for API that are highly water-soluble, which have been difficult to release in a controlled manner. It would be desirable to provide appropriate manufacturing processes to achieve all of these things.